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Viral infection: a potent barrier to transplantation tolerance.

Miller DM, Thornley TB, Greiner DL, Rossini AA - Clin. Dev. Immunol. (2008)

Bottom Line: Emerging as some of the most promising approaches for the induction of tolerance are protocols based on costimulation blockade.However, as these protocols move into the clinic, there is recognition that little is known as to their safety and efficacy when confronted with environmental perturbants such as virus infection.In animal models, it has been reported that virus infection can prevent the induction of tolerance by costimulation blockade and, in at least one experimental protocol, can lead to significant morbidity and mortality.

View Article: PubMed Central - PubMed

Affiliation: Division of Diabetes, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.

ABSTRACT
Transplantation of allogeneic organs has proven to be an effective therapeutic for a large variety of disease states, but the chronic immunosuppression that is required for organ allograft survival increases the risk for infection and neoplasia and has direct organ toxicity. The establishment of transplantation tolerance, which obviates the need for chronic immunosuppression, is the ultimate goal in the field of transplantation. Many experimental approaches have been developed in animal models that permit long-term allograft survival in the absence of chronic immunosuppression. These approaches function by inducing peripheral or central tolerance to the allograft. Emerging as some of the most promising approaches for the induction of tolerance are protocols based on costimulation blockade. However, as these protocols move into the clinic, there is recognition that little is known as to their safety and efficacy when confronted with environmental perturbants such as virus infection. In animal models, it has been reported that virus infection can prevent the induction of tolerance by costimulation blockade and, in at least one experimental protocol, can lead to significant morbidity and mortality. In this review, we discuss how viruses modulate the induction and maintenance of transplantation tolerance.

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Related in: MedlinePlus

Modulation of regulatory mechanisms by virus infection. Regulatory T cells play a crucial role in transplantation tolerance to allogeneic organs. Regulatory mechanisms that prevent immune attack on allogeneic tissues may be compromised in the setting of viral infection by at least two mechanisms. Release of inflammatory cytokines by virus-infected cells can prevent the differentiation of uncommitted naive CD4+ T cells into Tregs. Naive CD4+ T cells can differentiate into regulatory T cells in the presence of TGF-β. However, in the presence of TGF-β and proinflammatory cytokines such as IL-6, and perhaps IL-21, naive T cells can be skewed to turn into effector T cells such as the IL-17-producing TH17 cells. In a separate mechanism, release of cytokines such as IL-6 by infected APCs can render alloreactive effector cells refractory to suppression by regulatory T cells.
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fig4: Modulation of regulatory mechanisms by virus infection. Regulatory T cells play a crucial role in transplantation tolerance to allogeneic organs. Regulatory mechanisms that prevent immune attack on allogeneic tissues may be compromised in the setting of viral infection by at least two mechanisms. Release of inflammatory cytokines by virus-infected cells can prevent the differentiation of uncommitted naive CD4+ T cells into Tregs. Naive CD4+ T cells can differentiate into regulatory T cells in the presence of TGF-β. However, in the presence of TGF-β and proinflammatory cytokines such as IL-6, and perhaps IL-21, naive T cells can be skewed to turn into effector T cells such as the IL-17-producing TH17 cells. In a separate mechanism, release of cytokines such as IL-6 by infected APCs can render alloreactive effector cells refractory to suppression by regulatory T cells.

Mentions: IL-6 isan MyD88-dependent cytokine that has emerged as a candidate mediator forimpairing regulatory T cell generation and function; its production isdiminished in untreated [119]—as well asLCMV-infected [120]—mice deficient inMyD88. CD4+ T cells develop a FoxP3+ regulatory T cell phenotypewhen they are activated in the presence of TGF-β. However, when CD4+ T cells areactivated in the presence of TGF-βand IL-6, this regulatory phenotype is suppressed and the cells develop aproinflammatory TH17 cell phenotype [121] (Figure 4). Therefore, virus infection may precipitate allograftrejection by preventing the generation of Tregs following costimulationblockade and instead favor development of proinflammatory effector T cells.


Viral infection: a potent barrier to transplantation tolerance.

Miller DM, Thornley TB, Greiner DL, Rossini AA - Clin. Dev. Immunol. (2008)

Modulation of regulatory mechanisms by virus infection. Regulatory T cells play a crucial role in transplantation tolerance to allogeneic organs. Regulatory mechanisms that prevent immune attack on allogeneic tissues may be compromised in the setting of viral infection by at least two mechanisms. Release of inflammatory cytokines by virus-infected cells can prevent the differentiation of uncommitted naive CD4+ T cells into Tregs. Naive CD4+ T cells can differentiate into regulatory T cells in the presence of TGF-β. However, in the presence of TGF-β and proinflammatory cytokines such as IL-6, and perhaps IL-21, naive T cells can be skewed to turn into effector T cells such as the IL-17-producing TH17 cells. In a separate mechanism, release of cytokines such as IL-6 by infected APCs can render alloreactive effector cells refractory to suppression by regulatory T cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2536507&req=5

fig4: Modulation of regulatory mechanisms by virus infection. Regulatory T cells play a crucial role in transplantation tolerance to allogeneic organs. Regulatory mechanisms that prevent immune attack on allogeneic tissues may be compromised in the setting of viral infection by at least two mechanisms. Release of inflammatory cytokines by virus-infected cells can prevent the differentiation of uncommitted naive CD4+ T cells into Tregs. Naive CD4+ T cells can differentiate into regulatory T cells in the presence of TGF-β. However, in the presence of TGF-β and proinflammatory cytokines such as IL-6, and perhaps IL-21, naive T cells can be skewed to turn into effector T cells such as the IL-17-producing TH17 cells. In a separate mechanism, release of cytokines such as IL-6 by infected APCs can render alloreactive effector cells refractory to suppression by regulatory T cells.
Mentions: IL-6 isan MyD88-dependent cytokine that has emerged as a candidate mediator forimpairing regulatory T cell generation and function; its production isdiminished in untreated [119]—as well asLCMV-infected [120]—mice deficient inMyD88. CD4+ T cells develop a FoxP3+ regulatory T cell phenotypewhen they are activated in the presence of TGF-β. However, when CD4+ T cells areactivated in the presence of TGF-βand IL-6, this regulatory phenotype is suppressed and the cells develop aproinflammatory TH17 cell phenotype [121] (Figure 4). Therefore, virus infection may precipitate allograftrejection by preventing the generation of Tregs following costimulationblockade and instead favor development of proinflammatory effector T cells.

Bottom Line: Emerging as some of the most promising approaches for the induction of tolerance are protocols based on costimulation blockade.However, as these protocols move into the clinic, there is recognition that little is known as to their safety and efficacy when confronted with environmental perturbants such as virus infection.In animal models, it has been reported that virus infection can prevent the induction of tolerance by costimulation blockade and, in at least one experimental protocol, can lead to significant morbidity and mortality.

View Article: PubMed Central - PubMed

Affiliation: Division of Diabetes, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.

ABSTRACT
Transplantation of allogeneic organs has proven to be an effective therapeutic for a large variety of disease states, but the chronic immunosuppression that is required for organ allograft survival increases the risk for infection and neoplasia and has direct organ toxicity. The establishment of transplantation tolerance, which obviates the need for chronic immunosuppression, is the ultimate goal in the field of transplantation. Many experimental approaches have been developed in animal models that permit long-term allograft survival in the absence of chronic immunosuppression. These approaches function by inducing peripheral or central tolerance to the allograft. Emerging as some of the most promising approaches for the induction of tolerance are protocols based on costimulation blockade. However, as these protocols move into the clinic, there is recognition that little is known as to their safety and efficacy when confronted with environmental perturbants such as virus infection. In animal models, it has been reported that virus infection can prevent the induction of tolerance by costimulation blockade and, in at least one experimental protocol, can lead to significant morbidity and mortality. In this review, we discuss how viruses modulate the induction and maintenance of transplantation tolerance.

Show MeSH
Related in: MedlinePlus